Poor water solubility of active pharmaceutical ingredients (APIs) increasingly poses challenges to drug development, with >70% of new APIs suffering from this issue. Cocrystallization is a novel strategy for overcoming these challenges particularly for those APIs that are not readily derivatized with hydrophilic groups. Improvements to high throughput screening (HTS) for cocrystallization will expand the number of readily soluble, new chemical entities for API formulation, and will give Public Health benefit deriving from new, safer, and more bioavailable pharmaceuticals. The goal of this Phase I grant is to develop improved methods for API co-crystal screening that incorporate complementary crystallization approaches: (1) multiplexed mechanochemical solid state compression with shear, and (2) HTS compatible solution crystallization technologies that use surface chemistry modifications to give nucleation enhancements that improve crystallization outcomes. By incorporating these orthogonal crystal nucleation approaches into a unified workflow, the probability and speed of co-crystal formation in HTS screening efforts can be improved. DeNovX will demonstrate the utility of both multiplexed direct compression solid synthesis and minidrop solution crystallization using innovative surface assisted nucleation in 96 well HTS plates. Objectives for Phase II include quantitation of the integrated workflow efficiencies using 96 and 384 well HTS and an emphasis on more diverse synthons with the goal of using HTS handling and analytical methods to generate new cocrystal compositions that are relevant to unmet needs in pediatric and select orphan indications.